Neurohistin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEUROHISTIN

Composition:

Active substance: betahistine dihydrochloride;

One tablet contains betahistine dihydrochloride 8 mg, 16 mg, or 24 mg;

Excipients: povidone K 90; microcrystalline cellulose; lactose monohydrate; colloidal anhydrous silicon dioxide; crospovidone (type A); stearic acid.

Pharmaceutical form. Tablets.

Main physicochemical properties:

8 mg tablets: cylindrical, flat tablets with bevelled edges on both sides, marked with "B 8" on one side, smooth on the other.

16 mg tablets: cylindrical, flat tablets with bevelled edges on both sides, marked with "B 16" on one side, smooth on the other.

24 mg tablets: cylindrical, flat tablets with bevelled edges on both sides, marked with "B 24" on one side, smooth on the other.

Pharmacotherapeutic group. Agents for the treatment of vestibular disorders. Betahistine.

ATC code N07CA01.

Pharmacological properties.

Pharmacodynamics.

The mechanism of action of betahistine has been only partially elucidated. Several plausible hypotheses have been confirmed by data from studies conducted in animals and humans.

Effect of betahistine on the histaminergic system

Betahistine has been shown to act as a partial agonist at H1-receptors and as an antagonist at presynaptic H3-receptors of histamine in nervous tissue, with negligible activity at H2-histamine receptors. Betahistine increases histamine turnover and release by blocking presynaptic H3-receptors and inducing down-regulation of corresponding H3-receptors.

Betahistine may increase blood flow in the cochlear region and throughout the entire brain

Improvement in blood flow in the vessels of the stria vascularis of the inner ear may be due to relaxation of precapillary sphincters in the microcirculatory system of the inner ear. Betahistine also increases cerebral blood flow in humans.

Betahistine promotes vestibular compensation

Betahistine accelerates recovery of vestibular function after unilateral neurectomy in animals by stimulating and facilitating the process of central vestibular compensation. This effect is characterized by enhanced regulation of histamine turnover and release, mediated via H3-receptor antagonism. In humans, treatment with betahistine also reduced the recovery time of vestibular function following neurectomy.

\u<Betahistine alters neuronal activity in the vestibular nuclei

It has also been established that betahistine exerts a dose-dependent inhibitory effect on spike generation in neurons of the medial and lateral vestibular nuclei.

The pharmacodynamic properties of betahistine may provide a positive therapeutic effect on the vestibular system.

The efficacy of betahistine has been demonstrated in patients with vestibular vertigo and Ménière’s disease, as evidenced by a reduction in the severity and frequency of vertigo attacks.

Pharmacokinetics.

\uAbsorption\u

After oral administration, betahistine is rapidly and almost completely absorbed throughout all segments of the gastrointestinal tract. Following absorption, the drug is rapidly and almost completely metabolized to the metabolite 2-pyridylacetic acid. Plasma concentrations of unchanged betahistine are very low. Therefore, all pharmacokinetic analyses are performed by measuring the plasma and urinary concentrations of the metabolite 2-pyridylacetic acid.

When the drug is taken with food, the maximum concentration (Cmax) of the drug is lower than when taken on an empty stomach. However, the total extent of betahistine absorption is identical in both cases, indicating that food intake only delays the absorption process.

\uDistribution\u

The percentage of betahistine bound to plasma proteins is less than 5%.

\uBiotransformation\u

Following absorption, betahistine is rapidly and almost completely metabolized to 2-pyridylacetic acid, which has no pharmacological activity.

After oral administration of betahistine, the plasma (and urinary) concentration of 2-pyridylacetic acid reaches its maximum within 1 hour after dosing and declines with an elimination half-life of approximately 3.5 hours.

\uExcretion\u

2-Pyridylacetic acid is rapidly excreted in urine. After administration of betahistine in doses of 8–48 mg, approximately 85% of the initial dose is recovered in urine. Renal or fecal excretion of unchanged betahistine is negligible.

\uLinearity\u

The elimination rate remains constant following oral doses of 8–48 mg, indicating linear pharmacokinetics of betahistine and suggesting that the metabolic pathway involved is not saturable.

Clinical characteristics.

Indications.

Meniere's disease and Meniere's syndrome, characterized by three main symptoms:

• vertigo, sometimes accompanied by nausea and vomiting;
• hearing loss (deafness);
• tinnitus.

Symptomatic treatment of vestibular vertigo of various origins.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Pheochromocytoma.

Interaction with other medicinal products and other forms of interaction.

In vivo studies with other medicinal products have not been conducted. Based on in vitro data, inhibition of cytochrome P450 enzyme activity in vivo is not expected.

In vitro data indicate that the metabolism of betahistine is inhibited by drugs which inhibit monoamine oxidase (MAO) activity, including MAO subtype B (e.g., selegiline).

There have been reports of interactions with ethanol, with substances containing pyrimethamine, with dapsone, as well as potentiation of the effect of betahistine in the presence of salbutamol.

Caution is recommended when betahistine is used concomitantly with MAO inhibitors (including β-selective MAO inhibitors).

Since betahistine is a histamine analogue, interaction between betahistine and antihistamine medicinal products may affect the efficacy of one of these agents.

Special precautions for use

Patients with bronchial asthma and/or a history of peptic ulcer of the stomach and duodenum should be carefully monitored during treatment with this medicinal product.

Caution is recommended when treating patients with urticaria, skin rashes, or allergic rhinitis with betahistine, as there is a possibility of exacerbation of symptoms of these conditions.

Caution is recommended when treating patients with severe hypotension.

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of betahistine in pregnant women.

Animal studies have not shown any direct or indirect harmful effects on reproductive toxicity at doses corresponding to those used in clinical practice. Betahistine should not be used during pregnancy except in cases of clear medical need.

Breastfeeding period

It is unknown whether betahistine passes into human breast milk. Betahistine passes into the milk of rats. Studies in animals on the passage of betahistine into milk have not been conducted. Effects observed postpartum in animal studies were associated only with very high doses. The benefit of using the medicinal product for the mother should be weighed against the advantages of breastfeeding and the potential risk to the infant.

Fertility

Animal studies in rats did not reveal any effects on fertility.

Ability to influence reaction speed while driving or operating machinery

Betahistine is indicated for the treatment of Ménière's syndrome, characterized by the triad of vertigo, hearing loss, and tinnitus, as well as for symptomatic treatment of vestibular vertigo. Both conditions may negatively affect the ability to drive a vehicle or operate machinery. According to clinical studies investigating the effect of the medicinal product on the ability to drive and operate machinery, betahistine had no effect or only a negligible effect on this ability.

Cases of somnolence have been reported during betahistine treatment. Patients should avoid activities requiring concentration, such as driving a vehicle or operating machinery.

Dosage and administration.

The initial dose for adults, including elderly patients, is 8–16 mg, evenly divided into three daily doses taken with meals. Tablets should be swallowed whole with water.

The maintenance dose is 24–48 mg per day.

The dose should be individually adjusted according to the response. Symptom improvement may sometimes be observed only after two to three weeks of treatment. Optimal results may be achieved with several months of continuous treatment. There is evidence that initiating treatment at the early stages of the disease may prevent its progression and/or hearing loss at various stages.

Neuropresitin can be administered independently of food intake. During treatment, mild gastrointestinal disturbances (listed in section "Adverse Reactions") may occur, which can be alleviated by taking the medication with food.

Elderly patients

Although clinical data in this patient group are limited, extensive post-marketing experience with betahistine allows the assumption that dose adjustment is not required in this population.

Renal impairment

Specific clinical trials have not been conducted in this patient group; however, based on post-marketing experience with betahistine, dose adjustment is not required.

Hepatic impairment

Specific clinical trials have not been conducted in this patient group; however, based on post-marketing experience with betahistine, dose adjustment is not required.

Children

Due to insufficient data on safety and efficacy, Neuropresitin is not recommended for use in children (under 18 years of age).

Overdose

There have been a few reported cases of overdose. Mild to moderate symptoms (nausea, drowsiness, abdominal pain) were observed in some patients after ingestion of doses up to 640 mg.

More severe complications (seizures, cardiopulmonary complications) have been observed following intentional ingestion of high doses of betahistine, particularly when combined with overdose of other medicinal products.

Management of overdose should include standard supportive measures.

Side effects

The adverse reactions listed below were observed in patients treated with Neurohistin during placebo-controlled studies, with the following frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Gastrointestinal disorders

Complaints of mild gastrointestinal disturbances (nausea, gastrointestinal pain, bloating and flatulence). These side effects usually resolve when the medication is taken with food or after dose reduction.

Common: nausea, dyspepsia.

Nervous system disorders

Common: headache, somnolence.

In addition to events reported during clinical trials, the following adverse reactions have been reported spontaneously during post-marketing use and are known from scientific literature. Based on available data, the frequency cannot be estimated and is therefore classified as unknown.

Immune system disorders

Hypersensitivity reactions, e.g. anaphylaxis.

Skin and subcutaneous tissue disorders

Skin and subcutaneous tissue hypersensitivity reactions, including angioneurotic edema, rash, pruritus and urticaria.

Cardiovascular system disorders

Increased heart rate.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging, in a place protected from moisture.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Catalent Germany Schoorndorf GmbH.

Manufacturer's address.

Steinbeisstraße 1 and 2, Schoorndorf, Baden-Württemberg, 73614, Germany.